1. Field of the Invention
This invention relates to a series of novel amino acid, di- and polypeptide analogs which exhibit selective inhibition of interleukin-1.beta.-converting enzyme, to compositions containing the novel amino acid analogs and methods for therapeutic utility. More particularly, the interleukin-1.beta.-converting enzyme inhibitors described in this invention comprise novel .alpha.-substituted methyl ketones which possess particular utility in the treatment of inflammatory and immune-based diseases of lung, central nervous system, and connective tissues.
2. Reported Developments
Interleukin-1.beta. protease (also known as interleukin-1.beta.-converting enzyme or ICE) is the enzyme responsible for processing of the biologically inactive 31 kD precursor IL-1.beta. to the biologically active 17 kD form (Kostura, M. J.; Tocci, M. J.; Limjuco, G.; Chin, J.; Cameron, P.; Hillman, A. G.; Chartrain, N. A.; Schmidt, J. A. Proc. Nat. Acad. Sci. 1989, 86, 5227-5231 and Black, R. A.; Kronheim, S. R.; Sleath, P. R. FEBS Let., 1989, 247, 386-391). In addition to acting as one of the body's early responses to injury and infection, IL-1.beta. has also been proposed to act as a mediator of a wide variety of diseases, including rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, sepsis, and acute and chronic myelogenous leukemia (Dinarello, C. A.; Wolff, S. M., New Engl. J. Med., 1993, 328, 106). The naturally occurring IL-1.beta. receptor antagonist has been used to demonstrate the intermediacy of IL-1.beta. in a number of human diseases and animal models (Hannum, C. H.; Wilcox, C. J.; Arend, W. P.; Joslin, G. G.; Dripps, D. J.; Heimdal, P. L.; Armes, L. G.; Sommer, A.; Eisenberg, S. P.; Thompson, R. C., Nature, 1990, 343, 336-340; Eisenberg, S. P.; Evans, R. J.; Arend, W. P.; Verderber, E.; Brewer, M. T.; Hannum, C. H.; Thompson, R. C., Nature 1990, 343, 341-346; Ohlsson, K.; Bjork, P.; Bergenfeldt, M.; Hageman, R.; Thompson, R. C., Nature., 1990, 348, 550-552; and Wakabayashi, G., GASEB, 1991, 338-343). The specific role of IL-1.beta. in inflammation and immunomodulation is supported by the recent observation that the cowpox virus employs an inhibitor of ICE to suppress the inflammatory response of its host (Ray, C. A. et al, Cell, 1992, 69, 597-604).
The utility of ICE inhibitors in modifying certain IL-1.beta. mediated disease states has been suggested and demonstrated in vivo by several workers in the field. The following review of the current state of the art in ICE research further supports such utility of ICE inhibitors:
1) WO 9309135, published 11 May 1993, teaches that peptide-based aspartic acid arylacyloxy-and aryoxymethyl ketones are potent inhibitors of ICE in vitro. These compounds also specifically inhibited ICE in the whole cell (in vivo) by their ability to inhibit the formation of mature IL-1.beta. in whole cells. These ICE inhibitors also demonstrated utility in reducing fever and inflammation/swelling in rats. PA0 2) Patients with Lyme disease sometimes develop Lyme arthritis. B. burgdorferi, the causative agent of Lyme disease, is a potent inducer of IL-1.beta. synthesis by mononuclear cells. Miller et al. (Miller, L. C.; Lynch, E. A. Isa, S.; Logan, J. W.; Dinarello, C. A.; and Steere, A. C., "Balance of synovial fluid IL-1.beta. and IL-1.beta. Receptor Antagonist and Recovery from Lyme arthritis", Lancet (1993) 341; 146-148) showed that in patients who recovered quickly from Lyme Arthritis, the balance in synovial fluid of IL-1-beta and IL-1ra was in favor of IL-ra. When the balance was shifted in favor of IL-1.beta., it took significantly longer for the disease to resolve. The conclusion was that the excess IL-1ra blocked the effects of the IL-1.beta. in the patients studied. PA0 3) IL-1 is present in affected tissues in ulcerative colitis in humans. In animal models of the disease, IL-1.beta. levels correlate with disease severity. In the model, administration of 1L-1ra reduced tissue necrosis and the number of inflammatory cells in the colon. See, Cominelli, F.; Nast, C. C.; Clark, B. D.; Schindler, R., Llerena, R.; Eysselein, V. E.; Thompson, R. C.; and Dinarello, C. A.; "lnterleukin-1 Gene Expression, Synthesis, and Effect of Specific IL-1 Receptor Blockade in Rabbit Immune Complex Colitis" J. Clin. Investigations (1990) Vol. 86, pp, 972-980. PA0 4) IL-1ra supresses joint swelling in the PG-APS model of arthritis in rats. See Schwab, J. H.; Anderie, S. K.; Brown, R. R.; Dalldorf, F. G. and Thompson, R. C., "Pro- and Anti-Inflammatory Roles of Interelukin-1 in Recurrence of Bacterial Cell Wall-Induced Arthritis in Rats". Infect. Immun. (1991) 59; 4436-4442. PA0 5) IL-1ra shows efficacy in an small open-label human Rheumatoid Arthritis trial. See, Lebsack, M. E.; Paul, C. C.; Bloedow, C. C.; Burch, F. X.; Sack, M. A.; Chase, W., and Catalano, M. A. "Subcutaneous IL-1 Receptor Antagonist in Patients with Rheumatoid Arthritis", Arth. Rheum. (1991) 34; 545. PA0 6) IL-1 appears to be an autocrine growth factor for the proliferation of chronic myelogenous leukemia cells. Both IL-1ra and slL-1R inhibit colony growth in cells removed from leukemia patients. See, Estrov, Z.; Kurzrock, R.; Wetzler, M.; Kantarjian, H.; Blake, M.; Harris, D.; Gutterman, J. U.; and Talpaz, M., "Supression of Chronic Myelogenous Leukemia Colony Growth by Interleukin-1 (IL-1) Receptor Antagonist and Soluble IL-1 Receptors: a Novel Application for Inhibitors of IL-1 Activity". Blood (1991) 78; 1476-1484. PA0 7) IL-1 was also found to be a potent bone resorptive agent capable, upon infusion into mice, of causing hypercalcemia and increase in bone resorptive surface. See, Sabatini, M. et al., PNAS 85:5235-5239, 1988. PA0 8) Reduction of inflammation and pyrexia was found in the rat by oral administration of SDZ 224-015, an inhibitor of the IL-1.beta. converting enzyme by Elford et al., Br. J. Pharmacol (England), June 1995, 115(4) p. 601-6.
The present invention also relates to the modulation of processing of IL-1.beta. for the treatment of rheumatoid arthritis. Levels of IL-1.beta. are known to be elevated in the synovial fluid of patients with the disease. Additionally, IL-1.beta. stimulates the synthesis of enzymes believed to be involved in inflammation, such as collagenase and PLA.sub.2, and produces joint destruction which is very similar to rheumatoid arthritis following intra-articular injection in animals.
A limited number of peptidyl methyl ketone analogs constitute a well-known class of compounds having Cysteine protease (papain, cathepsin B) inhibitory activity. These peptidyl methyl ketone analogs have been reviewed by D. Rich in Chapter 4 of "Proteinase Inhibitors", Barrett, A. J. and Salvensen, G., eds., Elsevier, 1986. More recently, a-aryloxy and a-arylacyloxy methyl ketones have also been described as inhibitors of cysteine protease (Krantz, A. et al, Biochemistry, 30, p. 4678-4687, 1991).
These peptide analogs, however, are essentially devoid of potency and selectivity in inhibiting ICE.
An effective therapy has yet to be developed for the treatment of IL-1.beta. mediated inflammatory diseases. Consequently, there is a need for therapeutic agents effective in the treatment and prevention of these diseases.